Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor

Koefoed, Klaus; Steinaa, Lucilla; Søderberg, Josefine Nielsen; Kjær, Ida; Jacobsen, Helle J.; Meijer, Per-Johan; Haurum, John S.; Jensen, Allan; Kragh, Michael; Andersen, Peter S.; Pedersen, Mikkel Wandahl

doi:10.4161/mabs.3.6.17955

Cited by 88 publications

(92 citation statements)

References 34 publications

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“…Furthermore, the activation of EGFR mAb-triggered MoAs may be improved by combinations of noncompetitive EGFR mAbs to artificially enhance the Ag density on the tumor cell surface. Thus, combinations of EGFR mAbs were demonstrated to enhance CDC (20), as well as EGFR internalization (49), a concept that is currently under evaluation in clinical studies. Alternatively, Fc engineering approaches improved Fc-mediated MoAs, such as ADCC or CDC, against target cells with low levels of EGFR expression (21, 50).…”

Section: Discussionmentioning

confidence: 99%

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

Derer

Bauer

Lohse

et al. 2012

The Journal of Immunology

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The epidermal growth factor receptor (EGFR) is a widely expressed Ag that is successfully targeted in tumor patients by mAbs or tyrosine kinase inhibitors. A clinical study in non-small cell lung cancer patients demonstrated a positive correlation between EGFR expression levels and the therapeutic efficacy of the EGFR mAb cetuximab. However, the impact of EGFR expression on the different mechanisms of action (MoAs) triggered by the EGFR mAb has not been defined. In this study, BHK-21 cells were stably transfected to express different EGFR levels, which were quantified by immunofluorescence and immunohistochemistry and compared with EGFR levels of clinical non-small cell lung cancer samples. These cells were used to systematically investigate the impact of target Ag expression levels on Fab- or Fc-mediated MoAs of EGFR mAb. A negative correlation between EGFR levels and potency of Fab-mediated MoA was observed. Interestingly, Ab-dependent cell-mediated cytotoxicity (ADCC) by NK cells, monocytes, or polymorphonuclear cells as well as complement-dependent cytotoxicity positively correlated with the number of EGFR molecules. In comparison with ADCC by mononuclear cells, polymorphonuclear cell-mediated ADCC and complement-dependent cytotoxicity required higher EGFR expression levels and higher mAb concentrations to trigger significant tumor cell killing. This correlation between EGFR expression levels and Fc-mediated MoA was confirmed in an independent panel of human tumor cell lines carrying diverse genetic alterations. Furthermore, RNA interference-induced knockdown experiments reinforced the impact of EGFR expression on tumor cell killing by EGFR mAb. In conclusion, these results suggest that EGFR expression levels may determine distinct patterns of MoAs that contribute to the therapeutic efficacy of EGFR mAb.

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Section: Discussionmentioning

confidence: 99%

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

Derer

Bauer

Lohse

et al. 2012

The Journal of Immunology

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“…Spleens were recovered and macerated through a 74-mm cell strainer (Corning) generating single-cell suspensions. Antibodies specific for IGF1R were cloned using the murine Symplex technology, as previously described by Koefoed and colleagues (30). The two anti-EGFR antibodies (1565, 1277) and the two anti-HER3 antibodies (5038, 5082) are described by Koefoed and colleagues.…”

Section: Production Of Antibodies and Antibody Mixturesmentioning

confidence: 99%

“…The two anti-EGFR antibodies (1565, 1277) and the two anti-HER3 antibodies (5038, 5082) are described by Koefoed and colleagues. (30) and Jacobsen and colleagues (35). Antibody mixtures were generated freshly prior to the individual experiments and mixed in ratios of 1:1 or 1:1:1 (w/w).…”

Section: Production Of Antibodies and Antibody Mixturesmentioning

confidence: 99%

“…It is likely that the above-described mechanism of cetuximab action is insufficient for efficient EGFR targeting due to the plasticity/promiscuity of the receptor. More effective EGFR targeting strategies are in clinical development, including mixtures of anti-EGFR antibodies that induce EGFR degradation and secondary effector enhanced antibodies (29)(30)(31)(32)(33). Whether or not these will turn out to be superior to cetuximab remains to be seen.…”

Section: Introductionmentioning

confidence: 99%

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Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

Kjær

Lindsted

Fröhlich

et al. 2016

Molecular Cancer Therapeutics

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Squamous cell carcinomas (SCC) arising in upper parts of the aerodigestive tract are among the leading causes of death worldwide. EGFR has been found to play an essential role in driving the malignancy of SCC of the upper aerodigestive tract (SCCUAT), but, despite this, clinical results using a range of different EGFR-targeted agents have been disappointing. Cetuximab is currently the only EGFR-targeted agent approved by the FDA for treatment of SCCUAT. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to better understand the underlying mechanisms of cetuximab resistance in SCCUAT, we established from cetuximab-sensitive models cell lines with acquired resistance to cetuximab by continuous selective pressure in vitro and in vivo. Our results show that resistant clones maintain partial dependency on EGFR and that receptor tyrosine kinase plasticity mediated by HER3 and IGF1R plays an essential role. A multitarget mAb mixture against EGFR, HER3, and IGF1R was able to overcome cetuximab resistance in vitro. To our surprise, these findings could be extended to include SCCUAT cell lines with intrinsic resistance to cetuximab, suggesting that the triad consisting of EGFR, HER3, and IGF1R plays a key role in SCCUAT. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in SCCUAT. Mol Cancer Ther; 15(7); 1614-26. Ó2016 AACR.

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“…A unique feature of Sym004 is its ability to mediate rapid EGFR internalization and subsequent degradation of internalized receptors via EGFR cross-linking ( 17,18 ). Preclinical studies with Sym004 showed both superior induction of tumor regression as compared with other EGFR-targeting antibodies and antitumor activity in models of acquired cetuximab resistance ( 7 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer

et al. 2015

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Tumor growth in the context of EGFR inhibitor resistance may remain EGFRdependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes signifi cant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confi rmed marked Sym004-induced EGFR downmodulation. MET gene amplifi cation emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFR S492R mutation that is predictive of cetuximab resistance. SIGNIFICANCE:Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into signifi cant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted. Cancer Discov; 5(6);[598][599][600][601][602][603][604][605][606][607][608][609]

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Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor

Abstract: (2011) Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor, mAbs, 3:6, 584-595,

Cited by 88 publications

References 34 publications

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer

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